Locus Biosciences

Locus Biosciences is a preclinical-stage pharmaceutical company, founded in 2015 and based in Research Triangle Park, North Carolina which aims to develop phage therapies based on CRISPR–Cas3 gene editing technology, as opposed to the more commonly used CRISPR-Case9, delivered by engineered bacteriophages,[2] under the trademark crPhage. The intended therapeutic target of crPhase is antibiotic-resistant bacterial infections.[1][2]

Locus Biosciences
IndustryPharmaceutical company
FoundedMay 22, 2015 (2015-05-22) in Raleigh, NC, USA
Founders
  • Paul Garofolo[1]
  • Nick Taylor
  • Dave Ousterout
  • Rodolphe Barrangou[1]
  • Charles Gersbach
  • Chase Beisel
  • Ahmed Gomaa
Headquarters
Morrisville, North Carolina
,
United States
BrandscrPhage
Websitewww.locus-bio.com

History

The company was founded as a spin-off from North Carolina State University (NCSU) in 2015 with a $5 million convertible note from the Chinese investor Tencent Holdings and North Carolina Biotechnology Center,[3] and licensed CRISPR patents from NCSU.[4][5]

In 2017, the company closed a $19 million Series A led by Artis Ventures, Tencent Holdings Ltd, and Abstract Ventures.[5][6]

In 2018, Locus acquired the high-throughput bacteriophage discovery platform from San Francisco-based phage therapy company Epibiome, Inc.[7]

In 2019, the company entered into a strategic collaboration with Janssen Pharmaceuticals (a Johnson & Johnson company) worth up to $818 million to develop CRISPR-Cas3 drugs targeting two bacterial pathogens.[8][9][5][10]

Under the terms of the partnership, Locus will receive $20M upfront and up to $798M in milestones and royalties on net sales.[11]

Phage injecting its genome into bacterial cell

Differences between CRISPR CAS 3 and other subtypes
Main article: CRISPR

CRISPR-Cas3 is more destructive than the better known CRISPR–Cas9 used by companies like Caribou Biosciences, Editas Medicine, Synthego, Intellia Therapeutics, CRISPR Therapeutics and Beam Therapeutics.[5] CRISPR–Cas3 destroys the targeted DNA in either prokaryotic or eukaryotic cells.[8][12] Co-founder, Rodolphe Barrangou, said "Cas3 is a meaner system...but if you want to cut a tree and get rid of it, you bring a chain saw, not a scalpel"[13]

CRISPR-Cas systems fall into two classes. Class 1 systems use a complex of multiple Cas proteins to degrade foreign nucleic acids. Class 2 systems use a single large Cas protein for the same purpose. Class 1 is divided into types I, III, and IV; class 2 is divided into types II, V, and VI.[14] The 6 system types are divided into 19 subtypes.[15] Many organisms contain multiple CRISPR-Cas systems suggesting that they are compatible and may share components.[16][17]

Difference between CRISPR-Cas3 and CRISPR-Cas9
ClassCas typeSignature proteinFunctionReference
1ICas3Single-stranded DNA nuclease (HD domain) and ATP-dependent helicase[18][19]
2IICas9Nucleases RuvC and HNH together produce DSBs, and separately can produce single-strand breaks. Ensures the acquisition of functional spacers during adaptation.[20][21]

Clinical trial

The company enrolled its first patient in a Phase 1b clinical trial in January, 2020. The trial intends to evaluate LBP-EC01, a CRISPR Cas3-enhanced bacteriophage against Escherichia coli bacteria which cause urinary tract infections.[22] Twenty patients will get a phage cocktail, and 10 will get a placebo.[23]

gollark: It's not a megameter, it's 2.41Mm.
gollark: Thank you for your pointful response, bot.
gollark: I do have 2 feet, yes.
gollark: That should be in yottametres. Ridiculous.
gollark: 10000000000000000000000000000000000000 miles

References
  1. Buhr, Sarah (21 December 2018). "Move over Cas9, CRISPR-Cas3 might hold the key to solving the antibiotics crisis". TechCrunch. Archived from the original on 2019-02-20. Retrieved 2020-07-18.
  2. Gibney, Elizabeth (January 2, 2018). "What to expect in 2018: science in the new year". Nature. 553 (7686): 12–13. Bibcode:2018Natur.553...12G. doi:10.1038/d41586-018-00009-5. PMID 29300040.
  3. Martz, Lauren (31 August 2017). "Cutting through resistance". Biocentury. Retrieved 2020-07-18.
  4. Brown, Kristen V. (24 February 2017). "Scientists Are Creating a Genetic Chainsaw to Hack Superbug DNA to Bits". Gizmodo. G/O Media. Archived from the original on 2018-12-09. Retrieved 2020-07-18.
  5. "Up to $818 million deal between J&J and Locus Biosciences points to a new path for CRISPR therapies". Archived from the original on 2019-02-03. Retrieved 2019-03-08.
  6. Martz, Lauren. "Cutting Through Resistance". Biocentury.
  7. "Locus Biosciences Acquires EpiBiome Bacteriophage Discovery Platform". Genomeweb. July 17, 2018. Retrieved February 27, 2019.
  8. Taylor, Phil (3 January 2019). "J&J takes stake in Locus' CRISPR-based 'Pac-Man' antimicrobials". Fierce Biotech. Archived from the original on 6 March 2019. Retrieved 27 February 2019.
  9. "Antibiotics Are Failing Us. Crispr is Our Glimmer of Hope". Wired. 2019-01-16. Archived from the original on 2019-01-23. Retrieved 2019-03-08.
  10. "Is Phage Therapy Here to Stay?". Scientific American: 50–57. Retrieved 23 October 2019.
  11. Brown, Kristen (January 3, 2019). "J&J Bets $20 Million on DNA Tool to Battle Infectious Bacteria". Bloomberg. Retrieved 27 February 2019.
  12. Reardon, Sara (2017). "Modified viruses deliver death to antibiotic-resistant bacteria". Nature. 546 (7660): 586–587. Bibcode:2017Natur.546..586R. doi:10.1038/nature.2017.22173. PMID 28661508.
  13. Marcus, Amy Dockser. "A Genetic 'Chain Saw' to Target Harmful DNA". Wall Street Journal. Archived from the original on 6 March 2018. Retrieved 27 February 2019.
  14. Wright AV, Nuñez JK, Doudna JA (January 2016). "Biology and Applications of CRISPR Systems: Harnessing Nature's Toolbox for Genome Engineering". Cell. 164 (1–2): 29–44. doi:10.1016/j.cell.2015.12.035. PMID 26771484.
  15. Westra ER, Dowling AJ, Broniewski JM, van Houte S (November 2016). "Evolution and Ecology of CRISPR". Annual Review of Ecology, Evolution, and Systematics. 47 (1): 307–331. doi:10.1146/annurev-ecolsys-121415-032428.
  16. Wiedenheft B, Sternberg SH, Doudna JA (February 2012). "RNA-guided genetic silencing systems in bacteria and archaea". Nature. 482 (7385): 331–8. Bibcode:2012Natur.482..331W. doi:10.1038/nature10886. PMID 22337052.
  17. Deng L, Garrett RA, Shah SA, Peng X, She Q (March 2013). "A novel interference mechanism by a type IIIB CRISPR-Cmr module in Sulfolobus". Molecular Microbiology. 87 (5): 1088–99. doi:10.1111/mmi.12152. PMID 23320564.
  18. Sinkunas T, Gasiunas G, Fremaux C, Barrangou R, Horvath P, Siksnys V (April 2011). "Cas3 is a single-stranded DNA nuclease and ATP-dependent helicase in the CRISPR/Cas immune system". The EMBO Journal. 30 (7): 1335–42. doi:10.1038/emboj.2011.41. PMC 3094125. PMID 21343909.
  19. Huo Y, Nam KH, Ding F, Lee H, Wu L, Xiao Y, Farchione MD, Zhou S, Rajashankar K, Kurinov I, Zhang R, Ke A (September 2014). "Structures of CRISPR Cas3 offer mechanistic insights into Cascade-activated DNA unwinding and degradation". Nature Structural & Molecular Biology. 21 (9): 771–7. doi:10.1038/nsmb.2875. PMC 4156918. PMID 25132177.
  20. Gasiunas G, Barrangou R, Horvath P, Siksnys V (September 2012). "Cas9-crRNA ribonucleoprotein complex mediates specific DNA cleavage for adaptive immunity in bacteria". Proceedings of the National Academy of Sciences of the United States of America. 109 (39): E2579–86. Bibcode:2012PNAS..109E2579G. doi:10.1073/pnas.1208507109. PMC 3465414. PMID 22949671.
  21. Heler R, Samai P, Modell JW, Weiner C, Goldberg GW, Bikard D, Marraffini LA (March 2015). "Cas9 specifies functional viral targets during CRISPR–Cas adaptation". Nature. 519 (7542): 199–202. Bibcode:2015Natur.519..199H. doi:10.1038/nature14245. PMC 4385744. PMID 25707807.
  22. "Locus Biosciences initiates world's first controlled clinical trial for a CRISPR enhanced bacteriophage therapy". Retrieved 11 January 2020.
  23. "Scientists Modify Viruses With CRISPR To Create New Weapon Against Superbugs". NPR. 22 May 2019. Retrieved 28 May 2019.
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